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# Methylene Diphenyl Diisocyanate (monomeric MDI) and polymeric MDI (PMDI) (CASRN 101-68- 8, 9016-87-9)

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0529
Methylene Diphenyl Diisocyanate (monom eric MDI) and polymeric MDI (PMDI); CASRN 101-68-8, 9016-87-9 (02/07/1998)

Health assessment information on a chemical su bstance is included in IRIS only after a comprehensive review of chroni c toxicity data by U.S. EPA health scientists from several Program Offices and the Office of Research and Development. The su mmaries presented in Sections I and II represent a consensus reached in the review process. Background information and explanations of the methods used to derive the values given in IRIS are provided in the Background Documents.
STATUS OF DATA FOR Methylene Diphenyl Diis ocyanate (monomeric MDI) and polymeric MDI (PMDI)

File First On-Line 05/01/1994 Search IRIS by Keyword

IRIS Summaries/Toxicological Reviews Entire IRIS Website List of IRIS Substances

Reference Dose for Chronic Oral Exposure ( RfD )

Note: A TOXICOLOGICAL REVIEW is available for this chemical in Adobe PDF Format (54 Pages, 154 Kbytes). Similar documents can be found in the Li st of Available IRIS Toxicological Reviews. Links to specific pages in the toxicological review are available th roughout this summary . To utilize this feature, your Web browser and Adobe program must be configured properly so the PDF displays within the browser window. If your browser and Adobe program need configuration, please go to EPA's PDF page for instructions.

Cate g or y ( section ) Status Last Revised Oral RfD Assessment (I.A.) No data Inhalation RfC Assessment (I.B.) On-line 02/07/1998 

## Integrated Risk Information System htt p ://www.e p a. g ov/iris/subst/0529.htm Last u p dated on Monda y, March 07
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### _I. Chronic Health Hazard Assessments for Noncarcinogenic Effects

_I.A. Reference Dose for Ch ronic Oral Exposure (RfD)
Methylene Diphenyl Diisocyanate (monom eric MDI) and polymeric MDI (PMDI) CASRN — 101-68-8, 9016-87-9 Last Revised — 02/07/1998

Not available at this time.

_I.B. Reference Concentration for Chronic Inhalation Exposure (RfC)
Methylene Diphenyl Diisocyanate (monom eric MDI) and polymeric MDI (PMDI) CASRN: 101-68-8, 9016-87-9 Primary Synonym: Diphenylmethane Diisocyanate Last Revised: 02/07/1998

__I.B.1. Inhalation RfC Summary

*Conversion Factors: MW=250.26 (monomericMDI). BMC10 (ADJ) was obtained by running the BMC software program using concentrations from the Reuzel et al. (1994b) study adjusted for 24 hours/day and 7 days per week. The THRESH polynomial regression model, developed by Clement International (1990), specific for quantal endpoints, was used in the BMC analysis. The BMC10 (HEC) was calculated for a particle: respiratory effect in the extrathoracic (ET) region. The RDDR (ET) with a particle MMAD of 0.68 um and sigma g of2.93, based on particle depositi on modeling as described in U.S. EPA (1994), Interim Policy for Particle Size and Limit C oncentration Issues in Inhalation Toxicity, was calculated using current RDDR software as 0.453. The default body weight (462 gm) for the male Wistar rat was taken from Table 4.5 (U.S. EPA, 1994a), Methods for Derivation of Inhalation Reference Concentrations and Applications of Inhalation Dosimetry, and used as input to the RDDR program. BM C10 (HEC) = BMC10 (ADJ) RDDR (ET) = 0.06 mg/cu.m. For further discussion ofthe RDDR and derivation of the RfC see Sections 5.2.2 and 5.2.3 of the To xicological Review (US EPA 1998).

__I.B.2. Principal and Supporti ng Studies (Inhalation RfC)

Reuzel, P.G.J., J.H.E. Arts, L.G. Lomax, et al . 1994b. Chronic inhalation and carcinogenicity study of respirable polymeric me thylene diphenyl diisocyanate (p olymeric MDI) aerosol in rats. Fundam. Appl. Toxicol. 22: 195-210.

Reuzel, P.G.J., J.H.E. Arts , M.H.M. Kuypers, and C. F. Kuper. 1990. Chronic toxicity/carcinogenicity inhalation study of po lymeric methylene diphenyl diisocyanate aerosol in rats (Final Report). Prepared by Civo Institute for the International Isocyanate Institute. Report No. V88.122. Carcinogenicity Assessment (II.) On-line 02/07/1998

Critical Effect Ex p osures* UF MF RfC

Hyperplasia of the olfactory epithelium

Reuzel et al., 1990, 1994b Benchmark concentration (BMC): BMC10 (ADJ): 0.14 mg/cu.m BMC10 (HEC): 0.06 mg/cu.m 100 1 6E-4 mg/cu.m 

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8/9/2011 http ://www.ep a. g ov/iris/subst/0529.htmSpecific-pathogen-free (SPF)-bred Wistar rats of the Cpb: WU strain (60/sex/exposure level) were exposed whole-body to ae rosols of polymeric methylene diphenyl diisocyanate (PMDI). The test material was a dark brown liquid with an average molecular we ight of about 400 and each batch received from th e manufacturer contained 47% monomeric MDI. The remaining 53% was described as "polymeric" MDI. [Note: PM DI refers to a mixture containing about 50% monomeric MDI and 50% trimeric species and hi gher molecular weight oligomers (Ulrich, 1983); this composition, which is very similar to that used in the workplace, renders the material semisolid and suitable for aerosol gene ration.] The test material was kept at room temperature under "common laboratory conditions." This is interpreted to mean that the test material was stored under an inert gas. If unpro tected, MDI reacts with water to form carbon dioxide.
The rats were exposed for 6 h/day, 5 days/week, for 24 mo to nominal exposure levels of 0, 0.2, 1.0, and 6.0 mg/c u.m. A satellite group of rats (1 0/sex/exposure level) was exposed similarly for 12 mo and examined histopathologica lly at the end of expo sure. The mean actual values as measured by gravime try were within plus or minus 10% of nominal values. Thus, nominal values will be used in the following di scussion.. The duration-adjusted exposure levels are 0, 0.036, 0.18, and 1.1 mg/cu.m. Particle si ze determinations were made weekly with a cascade impactor. The mass median aerodynami c diameter (MMAD) and geometric standard deviation (in parenthesis) corres ponding to the exposure levels were 0, 0.68 um (2.93), 0.70 um (2.46), and 0.74 um (2.31), respectively. Gross observations and organ weights were obtained on all animals. Histological observatio ns were made on the lungs, mediastinal lymph nodes, and nasal cavity (six levels) on all anim als and in Forty-three ot her tissues in controls and animals exposed to 6 mg/cu.m.
Histologic evidence of damage at the 24-month necropsy of th e main group involved the same tissues as at 12 months, althou gh the severity had increased in nasal and pulmonary tissues. Basal cell hyperplasia was evident in the olfa ctory epithelium of the nasal tract of males (14/60, 13/60, 26/60, and 32/60 at 0, 0.2, 1.0, and 6.0 mg/cu.m, respectively) and females (4/60, 8/60, 8/60, and 49/59 at 0, 0.2, 1.0, and 6.0 mg/cu. m, respectively). Statistical significance was reached in males at the mid an d high concentrations and only at the high concentration in females. It was often accomp anied by Bowman's gland hyperplasia, which was significant in males at 1 and 6 mg/cu.m. Olfactory epithelial degeneration was elevated significantly in males and females only at 6 mg/c u.m. In the lung, there was increased severity in the accumulation of pigment-la den macrophage in alveolar ductlumina (incidence in males: 0/60, 3/60, 21/60, and 60/60; fe males: 0/59, 1/60, 23/60, and 59/ 59) and in localized fibrotic changes (males: 1/60, 0/60, 9/60, and 44/ 60; females: 0/59, 0/ 60, 4/60, and 48/60). Localized alveolar duct epithelialization was in creased significantly in both males and females exposed to 1 and 6 mg/cu.m. Loca lized alveolar bronchiolization was significant in both sexes exposed to 6 mg/cu.m. Accumulation of yello w pigment in the mediastinal lymph nodes was noted in males (incidence: 0/59, 0/53, 9/51, and 50/58) and fe males (incidence: 0/53, 1/57, 3/50, and 43/55). The accumulation of macropha ge and the localization of tissue damage in the area of macrophage accumulati on suggest that the lung effect is due primarily to toxicity of the macrophage (with secondary damage), although some of th e effects were described as being distributed evenly throughout the lungs. There were no hist ological effects in any of the other organ systems examined.

The information obtained in this chronic st udy suggests that the NOAEL is 0.2 mg/cu.m (duration-adjusted concentrat ion = 0.036 mg/cu.m) and a LOAEL of 1.0 mg/cu.m (durationadjusted concentration = 0.18 mg/cu.m) for re spiratory tract effects in both pulmonary and extrathoracic regions. The RfC was derived usin g benchmark concentration (BMC) analysis on basal cell hyperplasia of the ol factory epithelium (males only). The BMC approach was used 

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8/9/2011 http ://www.ep a. g ov/iris/subst/0529.htmbecause it takes into consideration the shape of the concentration-response curve, whereas the NOAEL selection is based solely on study co ncentrations employed. Given the apparent sensitivity of the male to basal cell hyperplasia and the expression of an elevated incidence of both basal cell hyperplasia and ol factory degeneration at both th e mid and high concentrations, it is not possible to differentiate basal cell hyperplasia, on the basis of either the interim or final sacrifice histopathological results, as a compensa tory response to olfactory degeneration. Thus, it is prudent to regard basal cell hyperplasia as an adverse response. This critical effect was chosen over localized pu lmonary fibrosis because, after HE Cs are compared, the nasal effects would yield a more conservative RfC. Because the test mixture in the Reuzel et al. study (1990, 1994b) was of a composition that is typically us ed during polyurethane foam manufacturing, the results of this stud y are more relevant to potential ex posure of individuals in ambient environments than are those associated with the pure MDI used by Hoymann et al. (1995), whose study description and evalua tion follows. For this reason, the results of the Reuzel study were used in RfC derivation.
The THRESH polynomial regression model, develo ped by Clement Internat ional specifically for quantal endpoints was used in the BMC analysis . The model was used to calculate extra risk, defined as the fraction of animals that would respond to a dose among animals who otherwise would not respond. The model was run at two sp ecified levels of risk, 5% and 10%, using the concentrations and responses for nasal olfactory basal cell hyperplasia in male rats from the Reuzel et al. (1994b) study. Maximum likelihood estimates (MLE) and BMC values (i.e., lower 95% confidence bound on MLE) were derived for ea ch risk level. With both models at the 5% and 10% risk levels, the MLEs were 0.10 and 0.22 mg/cu.m, respective ly. Results from both models indicated that the BMCs provided accept able fits to the data. The goodness-of-fit p value was 0.09. The BMCs were 0.07 and 0.14 mg/cu.m, respectively. The BMC10 values for nasal olfactory degeneration and for basal cell hyperplasia were nearly identical (0.14 mg/cu.m versus 0.18 mg/cu.m, respectively).
The regional deposited dose ratio (RDDR) was ca lculated for each regi on of the respiratory system according to a computer program based on the rationale and empirical data described in U.S. EPA (1994b). The RDDRs for the part icles having a MMAD = 0.68 um and sigma g = 2.93 are 0.453 for the extrathoracic and 0.910 fo r the thoracic regions. The resulting BMC10 (HEC) associated with nasal effects is 0.06 mg/cu.m.
A chronic toxicity study also wa s conducted in female Wistar ra ts (80/exposure group) exposed to monomeric MDI in aerosol form to gravimetrica lly determined levels of 0.23, 0.70, and 2.05 mg/cu.m for 17 h/day, 5 days/week for 24 mo (Hoymann et al., 1995). The amount of monomer in each of the three groups, determin ed by chemical analysis, was 0.097, 0.549, and 1.75 mg/cu.m, respectively. It is likely that mo nomeric MDI reacted with water in the exposure atmosphere to form oligoureas, amines, and carb on dioxide. The nominal levels were used for calculation purposes because the exposure levels in the Reuzel et al. (1994b) study were based on gravimetric analysis. The duration-adjuste d values are 0.12, 0.35, and 1.04 mg/cu.m, respectively. The MMAD of the exposure part icles was about 1 um in each of the three exposure groups. Treatment-related and statisti cally significant pulmonary lesions found in animals exposed for two years were similar in natu re to those found in the Reuzel et al. (1990, 1994b) study. They included: (1 ) dose-related increase in fo cal/multifocal alveolar and bronchioalveolar hyperplasia, (2) dose- relate d increase in incidence of focal/multifocal interstitial fibrosis of lungs, and (3) dose-related multifocal accumulation of particle-laden and pigmented macrophage. Goblet cell hyperplasi a in the nose and focal/multifocal mucosal inflammatory cell infiltration was significantl y elevated above controls for the high-exposure group only. No other significant nasal effects were observed. The hi stopathologic effects correlated with a number of pulmonary function effects, particularly in the high-exposure group. Histopathologic observations in a satellit e group examined at 1 year were consistent 

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8/9/2011 http ://www.ep a. g ov/iris/subst/0529.htmwith the effects reported at 2 years.
A study LOAEL of 0.23 mg/cu.m is identified in this study for pulmonary effects only. There is no NOAEL

__I.B.3. Uncertainty and Modify ing Factors (Inhalation RfC)

UF = 100.
Three uncertainty factors (UF) were applied to the BMC10 (HEC): a 10 for intraindividual variation, 3 for the lack of reproductive data, and a 3 for interspecies variation inasmuch as dosimetric adjustments had been made. The two UFs of 3 each coalesce to a 10, yielding a total UF of 100.

MF = 1.
__I.B.4. Additional Studies/Comments (Inhalation RfC)
In a 13-week study, SPF-bred Wistar rats (30/sex/exposure level) were exposed to polymeric MDI aerosol (Reuzel et al., 1985b, 1994a). Poly meric MDI was in the form of a dark brown liquid that contained 52% monomeric MDI. Rats we re exposed to 4, 8, or 12 mg/cu.m of an aerosol of this liquid for 6 h/day, 5 days/week, for 13 weeks. This study demonstrated adverse effects in the lungs and nasal ca vity at levels of 4 mg/cu.m an d above. However, because of a lack of data on aerosol sizes, a quantitative LO AEL(HEC) cannot be derived. In addition, Wistar rats (15/sex/exposure level) were exposed to PMDI aerosol at actual levelsof 0.35, 1.4, or 7.2 mg/cu.m for 6 h/day, 5 days/week for 13 weeks (R euzel et al., 1985a, 1990, 1994a). The only exposure-related observation was an increase in yellowish-colore d alveolar macrophages in all animals of the high-exposure group, but there wa s no tissue reaction ev ident. The results of these shorter-term studies are consistent with the findings of the chronic study that subsequently was performed (Reuzel et al., 1990, 1994b).
Exposure to isocyanates is a leading cause of occupational asthma worldwide (Mapp, 1988). Because PMDI is used extensively in making fl exible polyurethane foam, there have been a number of case reports describing occupational asthma and hypersensitivity pneumonitis, but exposure levels are unknown (Zammit-Tabona et al., 1983; Konzen et al., 1966; Tanser et al., 1973; Zeiss et al., 1980; Malo and Zeiss, 1982; O'Brien et al., 1979; Mapp et al., 1985; Lob and Boillat, 1981; Baur et al., 1984; Vandenplas et al., 1993). Specific immunoglobulin E and G antibodies have been demonstrated in some o ccupationally exposed workers with a diagnosis of occupational asthma, but the presence of antibodies can occur without asthmatic symptoms (Cartier et al, 1989; Liss et al., 1988; Pezzini et al., 1984; and Tse et al., 1985). High exposure concentrations, such as might occur during a sp ill (Brooks, 1982), likely are a risk factor in human sensitization. The available human data co ncerning occupational exposure to PMDI/MDI, coupled with lack of knowledge about mechanism of action, are insufficient to identify exposure levels and scenarios responsible for isocyana te-induced sensitization. For this reason, PMDI/MDI-induced asthma could not be select ed as an endpoint for RfC derivation. Few occupational studies have examined exposure-response relati onships with resp ect to pulmonary function decline as a result of PMDI/MDI expo sure. This endpoint is of concern given the demonstration of chronic pulmonary function dec line in workers exposed to TDI (Diem et al., 1982) and derivation of an RfC for TD I based on this study (IRIS, 1994).
Musk et al. (1982), in a longitudinal study, fo llowed for 5 years 107 workers from two plants in a polyurethane manufacturing facility in which both TDI and MDI were present in the air. MDI was used only in the last 2 ye ars of the study. Th e geometric mean of the MDI measurements 

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8/9/2011 http ://www.ep a. g ov/iris/subst/0529.htmwas reported as 0.0003 and 0.0006 ppm in each of the two plants. The TDI levels were about twice the levels of MDI. Howeve r, MDI levels may have been much higher, as it has been demonstrated that MDI exists as an aeroso l, not a vapor (Dharmarajan and Weill, 1978). No adverse effects on pulmonary f unction, measured according to applicable criteria of the American Thoracic Society (ATS), were detected during the course of the study as measured by FEV1. Reanalysis of the data (Musk et al., 1985) confirmed the results and conclusions.
Pham et al. (1988) prospectively studied a group of workers from two polyurethane manufacturing facilities in 1976 and 1981. Exposu re levels were not well characterized and criteria for pulmonary function testing were no t cited. Attrition of females was high as 64% were lost to follow-up in 1981. Exposure catego ries were classified as: A--unexposed in both studies, B--indirectly exposed, C--directly exposed, and D-- exposed in 1976 but removed from contact with MDI in 1981. Although the number of workers with asthma or chronic bronchitis increased in all groups and functional impairmentwas observed in vital capacity and FEV1 in group C, the lack of exposure characterization, attrition, and inclusion of asthmatics preclude any conclusions with respect to MDI.
The potential of PMDI to cause developmental e ffects was examined in tw o inhalation studies. Buschmann et al. (1996) reported a possible deve lopmental effect when gravid Wistar rats were exposed to 1, 3, or 9 mg monomeric MDI/cu.m for 6 h/day from days 6-15 post conception, after which surviving animals were ne cropsied on day 20. A si gnificant increase in asymmetric sternebrae in fetuses from the high -exposure group was observed and regarded as a possible developmental effect. A quasi-mono disperse MDI aerosol was generated by a evaporation-condensation tech nique. The particles had a MMA D of 1.1 æm and a geometric standard deviation of 1.37. Polymerization was precluded by exposing MDI droplets to temperatures above 50øC to a period of 1.5 se c only during droplet evaporation. Prenatal toxicity was also evaluated in pr egnant Wistar rats exposed to respirable PMDI from days 6-15 of gestation (Gamer et al., 1994). Rats (25/exposu re level) were exposed to 1, 4, and 12 mg PMDI/cu.m with a MMAD below 2.8 um. Two trea tment-related deaths occurred in the highexposure group and some survivors in thisgroup exhibited respiratory symptoms. No treatment- related effects on gestational or fetal parameters occurred in the two lowest exposure groups. However, the increase in maternal lung we ights in these groups warrants concern about developmental effects postnatally.
While the Gamer et al. (1994) study suggests that the potential of PMDI to cause prenatal toxicity in this strain is low, studies in othe r laboratory animal species and a multigenerational study would be needed to ascertain the potent ial to cause functional deficits or altered development in the postnatal period. PMDI/MDI may have potential to reach extrarespiratory sites such as the testes and ov aries. Measurable radioactivity was found to reach extrathoracic tissues and body fluids of guinea pigs exposed for 1 h to radiolabeled TDI levels as low as 4 ppb (Kennedy et al., 1989).
For more detail on Susceptible Populations, exit to the toxicological review, Section 4.7 (PDF)

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__I.B.5. Confidence in the Inhalation RfC
Study — High Database — Medium RfC — Medium
Confidence in the principal study is high becaus e the study was well desi gned, performed in an adequate number of animals, and indicated a concentration-re sponse relationship for the 

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8/9/2011 http ://www.ep a. g ov/iris/subst/0529.htmcritical effect. Confidence in th e database is medium because of data limitations regarding (1) developmental effects in the postnatal period and reproductive parameters in laboratory animals, (2) incomplete characterization of ac tive agent(s) in test atmospheres, and (3) exposure-response data for PMDI/MDI-induced asthma. Although studies with TDI have not shown any reproductive or deve lopmental effects (Tyl, 1988; Tyl and Neeper-Bradley, 1989), the potential for PMDI/MDI to cause such effect s has not been established. The RfC is given a medium confidence rating beca use (1) confidence in the data base takes precedence and (2) may not be sufficiently protective against isocyanate-induced asthma in individuals already sensitized to isocyanates.

For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, Section 6 (PDF)

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__I.B.6. EPA Documentation and Re view of the Inhalation RfC
Source Document: Toxicological Review of Methylene diphenyl diisocyanate in Support of Summary Information on Integrated Risk In formation System (IRIS). (US EPA 1998)
This assessment was peer reviewed by exte rnal scientists. Their comments have been evaluated carefully and incorporated in finalizatio n of this IRIS Summary. A record of these comments is included as an appendix to the Toxicological Review of Methylene Diphenyl Diisocyanate (MDI) US EPA 1998. To review this appendix, exit to the toxicological review, Appendix B, Summary of and Response to External Peer Review Comments (PDF)

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Other EPA Documentation None
Agency Consensus Date — 10/20/1997
Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology litera ture pertinent to the RfC for Methylene Diphenyl Diisocyanate (monomeric MDI) and polyme ric MDI (PMDI) conducted in November 2001 identified one or more significant new studies. IRIS users may request the references for those studies from the IRIS Hot line at hotline.iris@epa.gov or (202)566-1676.

__I.B.7. EPA Contacts (Inhalation RfC)
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1 749 (FAX), or hotline.iris@epa.gov (Internet address).



### _II. Carcinogenicity Assess ment for Lifetime Exposure
Methylene Diphenyl Diisocyanate (Monom eric MDI) and Polymeric MDI (PMDI) CASRN —101-68-8, 9016-87-9 Last Revised 02/07/1998
Section II provides information on three as pects of the carcinogenic assessment for the substance in question; the weight-of-evidence judgment of the likelihood that the substance is a human carcinogen and quantitative estimates of risk from oral exposure and from inhalation exposure. The quantitative risk estimates are pre sented in three ways. The slope factor is the result of application of a low- dose extrapolation procedure and is presented as the risk per 

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8/9/2011 http ://www.ep a. g ov/iris/subst/0529.htm(mg/kg)/day. The unit risk is the quantitative estimated in terms of either risk per ug/L drinking water or risk per ug/cu.m air breathed. The third form in which risk is presented is a drinking water or air concentration providing ca ncer risks of 1 in 10,000, 1 in 100,000, or 1 in 1,000,000. The rationale and methods used to deve lop the carcinogenicity information in IRIS are described in the Risk Assessment Guide lines of 1986 (EPA/600/8-87/045) and the IRIS Background Document. IR IS summaries developed since the pu blication of EPA's more recent Proposed Guidelines for Carc inogen Risk Assessment also utilize those Guidelines where indicated (Federal Register 61 (79):17960-18011, April 23, 1996). Users are referred to Section I of this IRIS file for information on long-t erm toxic effects other th an carcinogenicity.

_II.A. Evidence for Human Carcinogenicity
__II.A.1. Weight-of-Evidence Characterization

Under U.S. EPA's 1986 Guidelines for Carcin ogen Risk Assessment, monomeric MDI or polymeric MDI (PMDI) would be classified as not classifiable or a Group D chemical. Under U.S. EPA's 1996 Proposed Guidelines for Carcinogen Ri sk Assessment, the carc inogenic potential of MDI/PMDI would be characterized as "cannot be determined, but for which there is suggestive evidence that raises concern for carcinogenic effects" on the following basis. The increased incidence of pulmonary adenomas in male (6/6 0) and female (2/59) Wistar rats (strain Cpu:WU) and one pulmonary aden ocarcinoma in a male rat, all exposed to the highest concentration in a lifet ime chronic inhalation study involv ing PMDI, suggest that PMDI has tumorigenic potential. However, the finding of one pulmonary adenocar cinoma in a chronic study is not clear evidence of ca rcinogenic potential. However, the tumorigenic results, coupled with evidence that methylene diphenyl aniline (MDA), a known animal carcinogen and the principal reaction product of MDI, is found in blood of MDI-exposed rats and nonhydrolyzed urine of PMDI/MDI-exposed humans increases concern about the carcinogenic potential of PMDI/MDI. The available human evid ence is inadequate to describe the carcinogenic potential of PMDI/MDI.

For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, Section 6 (PDF)

. For more detail on Susceptible Populations, exit to the toxicological review, Section 4.7 (PDF)

. __II.A.2. Human Carcinogenicity Data
Inadequate. Two retrospective co hort mortality/cancer incidenc e studies were conducted to investigate associations between increased ca ncer risk and exposure to chemicals in polyurethane foam production workers (Sorahan and Pope, 1993; Hagmar et al., 1993a,b). Both populations were exposed to toluene diisocyanate (TDI), MDI, and other chemicals. No increased cancer risks attribut ed to isocyanate exposure were observed. Exposure to isocyanates was not well characterized and the study cohorts were expo sed to a variety of other chemicals. The average duration of empl oyment in the Hagmar et al. (1993a) study was 6.5 years with an average follow-up of 10.6 year s. In the Sorahan and Pope (1993) study, the minimum length of follow-up was 9 years. The young age of the cohorts and the short followup time limit a full evaluation of the carcinogen ic potential of this exposure environment.

__II.A.3. Animal Carcinogenicity Data
Limited. Four groups of 60 Wistar rats (strai n Cpb:WU) of each sex were exposed whole-body by inhalation to nominal levels of 0, 0.2, 1.0, or 6.0 mg/cu.m of PMDI aerosol for 6 h/day, 5 

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8/9/2011 http ://www.ep a. g ov/iris/subst/0529.htmdays/week for 24 mo (Reuzel et al., 1990, 1994a). [Note: PMDI re fers to a mixture containing about 50% monomeric MDI and 50% trimeric spec ies and higher molecular weight oligomers (Ulrich, 1983); this comp osition, which is very similar to th at used in the workplace, renders the material semisolid and suitable for aerosol generation]. The selection of 6 mg/cu.m as the high dose was based on a steep dose-response cu rve identified in a 13- week study (Reuzel et al., 1994b). In the latter study, severe respiratory effects, includ ing mortality, was observed at 12.3 mg/cu.m whereas similar, but much less seve re, clinical effects were seen at the next lowest dose, 8.4 mg/cu.m. These observations, coupled with sign ificant increases in absolute and relative lung weights in the chronic study, are consistent with 6.0 mg/cu.m in the chronic study as approaching a maximum tolerated dose.

Mean actual values were within ñ 10% of nomi nal values. The MDI test material was a dark brown viscous material, of which 47% was mono meric MDI. The remaining 53% was described as polymeric MDI. The material was stored un der "common laboratory conditions," which is interpreted to mean under an inert gas to prevent reaction with water. The mass mean aerodynamic diameter (MMAD) and geometric st andard deviation or sigma g (in parenthesis) corresponding to the exposure levels were 0, 0.68 um (2.93), 0.70 um (2.46), and 0.74 um (2.31), respectively. Forty-three different organsor tissues and all grossly visible lesions were examined by light microscopy of control and all high-concentration animal s and of decedents of the other concentration groups. Survivors of the low- and mid- concentration groups were subjected to histopathological examination of th e nose, lungs, mediastinal lymph nodes, and all gross lesions. Although olfactory epithelial de generation was elevated significantly in both sexes at 6 mg/cu.m and concentr ation-related increase basal ce ll hyperplasia was evident in males, there were no compound-related nasal tumors. Pulmonary adenom as were observed in males (6/60) and females (2/59) exposed to 6 mg/cu.m compared with controls (0/120). Also, one pulmonary adenocarcinoma (approximately 10 mm in size) was observed in one male exposed to 6 mg/cu.m. The aden omas were only a few millimeter s in size and were located adjacent to areas in which hemorrhage, macrop hage accumulations, and fibroblastic reactions were observed. These data suggest that recu rrent tissue injury may be requisite for the induction of tumors.
A chronic toxicity/carcinogenicity study also has been conducted in female Wistar rats, strain Crl:[WI]BR (Hoymann et al. 1995). In this unpublished study, rats were exposed to mean concentrations of monomeric MDI in aerosol fo rm of 0.23, 0.70, and 2.05 mg/cu.m. The MMAD was determined to be about 1 um in each of the three exposed groups. The selection of exposure levels was based on results of a pre vious 90-day study. The highest concentration can be considered a maximum tolerated dose inas much as the body weight gain for this group after 17 months of exposure was 11% less than th at of controls. Proliferation of the alveolar epithelium, considered preneoplastic, was observ ed along with bronchiola r- alveolar adenomas in the high-concentration group. Neither MDI- nor MDA-DNA addu cts were found in the lungs; however, the high dilution inherent in the techniques used may have been responsible for this "negative" finding.
Under the conditions of the Hoymann et al. (1995) study, in which about 85% of the material inhaled by the animals in the high-concentra tion group was monomeric MDI, there was no evidence of a tumorigenic resp onse in the lungs. Only one bronchioalveolar adenoma was found in 1/80 rats in the high-concentration group. The low incidence in females from the Reuzel et al. (1994) study and the lack of a response in females from the Hoymann et al. (1995) study may indicate that the female Wistar rat is not th e most appropriate test species for determination of the carcinogenic potential of PMDI or monomeric MDI. The difference in monomeric MDI content of inhaled material between the two studie s also represents a confounding factor. 

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8/9/2011 http ://www.ep a. g ov/iris/subst/0529.htm__II.A.4. Supporting Data for Carcinogenicity
Pulmonary adenomas have also been observed in mice, but not rats, exposed to TDI. Loeser (1983) exposed groups of Sprague-Dawley ratsand CD-1 mice to 0, 0.05, or 0.15 ppm TDI (80:20 mixture of the 2,4 and 2,6 isomers, resp ectively) for 6 h/day, 5 days/week, for 2 years. No treatment-related tumors were observed in rats. Although there was no difference in survival or body weight changes between controlsand exposed animals, rhinitis suggests that the maximum tolerated dose wa s approached. Although there was no dose-response trend, multiple pulmonary adenomas were elevated in male mice at 0.05 ppm (9/90, p=0.01, Fishers exact test; controls 1/90) and at 0.15 ppm ( 6/ 90, p=0.06, Fishers exac t test). The incidence of pulmonary carcinomas in male exposed mice was less than that of controls. Lymphomas of the haematopoietic/lymphoreticular system was also elevated in male, but not female, mice. The incidence in the 0.05 ppm group was 12/90 co mpared with 2/90 in controls and in the 0.15 ppm group, 5/90. The investigators did not consid er the lymphomas to be treatment- related. Although there was a variety of noncarcino genic nasal lesions in both sexes upon histopathology, no nasal tumors were observed. Mortality in mice at study termination was high in both sexes, but no treatment- rela ted effects in this regard were discerned.
MDI yielded mixed results in geno toxicity tests. Technical-grade monomeric MDI was positive in the Salmonella reverse mutation plate- incorpora tion assay in strains TA98 and TA100 only in the presence of exogenous metabolic activation an d negative in strain TA1537 (Anderson et al, 1980). A prepolymer [liquified, branched-chain MD I material formed by reaction of MDI with small amounts of glycols] of MDI tested similarl y although activity was much less than with the technical-grade material. Using a plate-incorpor ation assay, Haskell Laboratories (1976) also found monomeric MDI in the presence of metabolic activation to test positive with strains TA98 and TA100, but not TA1535 or TA1537. However, Zeiger et al . (1987) found MDI to test negative both with and without exogenous at co ncentrations up to 10,000 ug per plate in strains TA98, TA100, TA1535, and TA1537. All te st substances in the above-mentioned studies had been dissolved in dimethylsulfoxide (DMS O), a solvent in which MDI (and TDI) are unstable and may lead to genotoxic degradatio n products (Gahlmann et al., 1993). Hengler and Slesinski (1982) also reported negative resu lts for a "prepolymer" of MDI in these four strains in a plate-incorporation assay; howe ver, concentrations appear to have been considerable lower than those in the other studies. Positive contro ls tested appropriately for all strains.
A commercial grade of MDI (45% by weight MDI) without exogenous activation was found to induce chromosome aberrations in human wh ole-blood lymphocyte cultures after 24-hr treatment; addition of exogenous metabolic ac tivation significantly increases aberration frequency only at the highest concentratio n tested (Maki-Paakenen and Norpa, 1987).

_II.B. Quantitative Estimate of Carc inogenic Risk from Oral Exposure

No data available.

_II.C. Quantitative Estimate of Carcin ogenic Risk from Inhalation Exposure

No data available. 

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8/9/2011 http ://www.ep a. g ov/iris/subst/0529.htm__II.C.3. Additional Comments (Carcinogenicity, Inhalation Exposure)
The mechanism by which PMDI/MDI causes benign pulmonary tumors in Wistar rats (principally in males), a strain in which such tumors are ra re, chronically exposed to 6 mg/cu.m for 2 years is unknown. MDA may be a causat ive agent. This reaction produc t has been detected after acid hydrolysis in blood and amniotic fluid of pregnan t rats exposed to MDI (Bartsch et al., 1996) and in blood and nonhydrolyzed urine of PMDI-e xposed workers (Sepai et al., 1995). It has been shown to result in pulmonary adenomas (and tumors at remote sites) when MDA was administered to female mice in drinking water (Lamb et al., 1986). In addition, the pulmonary adenomas associated with TDI exposure (Loeser, 1983), an isocyanate of similar reactivity, occurred in mice, but not rats. In the absence of toxicity/car cinogenicity studies of mice exposed to PMDI/MDI, it is unclear if mice are si mply more sensitive than rats to the effects of such compounds. If so, the carc inogenic potential of polymeric MDI as reflected by the results of the studies in rats may be underestimated. On the other hand, Reuzel and coworkers, as well as Hoymann et al. (1995), suggest that these adenomas (and preneoplastic lesions observed by Hoymann et al.) may be the result of recurrent tissue damage since effects were seen in high- dose animals. This hypothesis finds support in the observation by Reuzel and coworkers that the adenomas are adjacent to areas of tissue damage.
__II.C.4. Discussion of Confidence (C arcinogenicity, Inhalation Exposure)
From a qualitative pers pective, the animal evidence for PMDI and MDA raises concern that PMDI/MDI may have tumorigenic/carcinogenic potential in human exposure scenarios. The inconclusive results associating lung cancer in occupational populations with exposure to TDI/MDI does not diminish this concern. The limit ations of the human studies, particularly the purportedly low levels of exposure and the short duration of exposure of the cohorts, preclude a more definitive assessment.

The two lifetime inhalation studies in which an appropriate number of rats were exposed to respirable PMDI and monomeric MDI yielded re sults that were similar in nature. Thus, confidence is high that the pulmonary effects observed were treatment-related. However, uncertainties surrounding mechan ism and dose preclude extrapolation to humans inasmuch as the agent (PMDI, monomeric MDI, or MDA) resp onsible for the tumorige nic response in the principal study is unknown.

_II.D. EPA Documentation, Review, and Contacts (Carcinogenicity Assessment)

__II.D.1. EPA Documentation
Source Document — Toxicologica l Review of Diphenylmethane Diisocyanate in Support of Summary Information on Integrated Risk In formation System (IRIS) (US EPA 1998).
This assessment was peer reviewed by exte rnal scientists. Their comments have been evaluated carefully and incorporated in finalizatio n of this IRIS Summary. A record of these comments is included as an appendix to To xicological Review of Methylene Diphenyl Diisocyanate (MDI) in support of summary info rmation on Integrated Risk Information System (IRIS). To review this appendix, exit to the toxicological review, Appendix B, Summary of and Response to External Peer Review Comments (PDF)

.

__ II.D.2. EPA Review ( Carcino g enicit y Assessment ) 

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8/9/2011 http ://www.ep a. g ov/iris/subst/0529.htmAgency Consensus Date — 10/20/1997
Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinen t to the cancer assessment for Methylene Diphenyl Diisocyanate (monomeric MDI) and polymeric MDI (PMDI) conducted in November 2001 did not identify any critical new studies. IRIS users wh o know of important new studies may provide that information to the IRIS Hot line at hotline.iris@epa.gov or (202) 566-1676.
__II.D.3. EPA Contacts (Car cinogenicity Assessment)
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1 749 (FAX), or hotline.iris@epa.gov (Internet address).



### _III. [reserved] _IV. [reserved] _V. [reserved]

_VI. Bibliography
Methylene Diphenyl Diisocyanate (monom eric MDI) and polymeric MDI (PMDI); CASRN 101-68-8, 9016-87-9 Last Revised 02/07/1998

_VI.A. Oral RfD References
Not applicable.

_VI.B. Inhalation RfC References

Baur, X., M. Dewair, and H. Rommelt. 1984. Acute airway obstruction followed by hypersensitivity pneumonitis in an isocyanate (MDI) worker. J. Occup. Med. 26(4): 285-287.

Brooks, S.M. 1982. The evaluati on of occupational airways di sease in the laboratory and workplace. J. Allergy Clin. Immunol. 70: 56-66.

Buschmann, J., W. Koch, R. Fuhst, and U. Heinrich. 1996. Embryotoxicity study of monomeric 4,4'-Methylenediphenyl Di isocyanate (MDI) aerosol after inha lation exposure in Wistar rats. Fund. Appl. Toxicol. 32: 96-101
Cartier, A., L. Gammer, J.-L. Malo, F. Lagier, H. Ghezzo, K. Harris, and R. Patterson. 1989. Specific serum antibodies against isocyanates: A ssociation with occupation al asthma. J. Allergy Clin. Immunol. 84: 507-514.
Clement International. 1990. THC: A computer program to compute a reference dose from 

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8/9/2011 http ://www.ep a. g ov/iris/subst/0529.htmquantal animal toxicity data using the benchm ark dose method. K.S. Crump Division, Ruston, LA.
Dharmarajan, V. and H. Weill. 1978. Physical state of ai rborne p,p'- diphenylmethane diisocyanate (MDI) and its measurement. Am. Ind. Hyg. Asso c. J. 39: 737-744.
Gamer, A.O., J. Hellwig, K. Kuttle r, and B. Hildebrand. 1994. Prenatal toxicity of polymeric MDI in rats: aerosol inhalation. BASF Aktiengesell schaft, Ludwigshafen/Rhein, FRG. Project No. 31R0354/92046.
Hoymann, H.-G., J. Buschmann , and U. Heinrich. 1995. Exam inations about the chronic toxicity/carcinogenicity of 4,4' -methylene diphenyl diisocyanate (MDI). Fraunhofer-Institut fur Toxikologie and Aerosolforschung, Hannover, Ge rmany. Report No. 1 16-06-084 (in German).
Kennedy, A. L., M. F. Stock, Y. Alarie, and W.R. Brown. 1989. Uptake and distribution of 14C during and following inhalation exposure to ra dioactive toluene diisocyanate. Toxicol. Appl. Pharmacol. 100: 280-292.

Konzen, R. B., B.F. Cr aft, L.D. Scheel, and C.H. Gors ki. 1966. Human response to low concentrations of p,p'-diphenylmethane diisocya nate (MDI). Am. Ind. Hyg. Assoc. J. 27(2): 121-127.

Liss, G.M., D.I. Bern stein, D.R. Moller, J.S. Gallagher, R.L. Stephens on, and I.L. Bernstein. 1988. Pulmonary and immunologic evaluation of foundry workers exposed to methylene diphenyldiisocyanate (MDI). J. A llergy Clin. Immunol. 82(1): 55-61.

Lob, M. and M.-A. Boillat. 1981. Asthme reta rde au diphenylmethane diisocyanate (MDI). Schweiz. Med. Wschr. 111: 150-154.
Malo, J.-L. and C.R. Zeiss. 1982. Occupational hy persensitivity pneumonitis after exposure to diphenylmethane diisocyanate. Am. Rev. Respir. Dis. 125: 113-116.
Mapp, C.E., L. Dal Vecchio, P. Boschetto, an d L.M. Fabbri. 1985. Combined asthma and alveolitis due to diphenylmethane diisocyana te (MDI) with demonstration of no crossed respiratory reactivity to toluene diisocyanate (TDI). Ann. Allergy 54: 424-429.
Mapp, C.E., P. Boschetto, L. Dal Vecchio, P. Maestrelli, and L.M. Fabbri. 1988. Occupational asthma due to isocyanates. Eur. Resp. J. 1: 273-279.

Musk, A.W., J.M. Peters, L. DiBerardinis, an d R.L.H. Murphy. 1982. Absence of respiratory effects in subjects exposed to low concentrations of TDI and MD I. J. Occup. Med. 24(10): 746- 750.

Musk, A.W., J.M. Peters, and L. Bernstein. 1985. Absence of re spiratory effects in subjects exposed to low concentrations of TDI and MDI: A reevaluation. J. Occup. Med. 27(12): 917- 920.
O'Brien, I.M., A.J. Newman-Taylor, P.S. Burge, M. G. Harries, I.W. Fawcett, and J. Pepys. 1979. Toluene diisocyanate-induced asthma: II. Inhala tion challenge tests an d bronchial reactivity studies. Clin. Allergy 9: 7-15.
Pezzini, A., A. Riviera, P. Pagg iaro, A. Spiazzi, F. Gerosa, M. Filieri, G. Toma, and G. Trident. 1984. Specific IgE antibodies in twenty-eightworkers with diisocyanate-induced bronchial 

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8/9/2011 http ://www.ep a. g ov/iris/subst/0529.htmasthma. Clin. Allergy 14: 453-461.

Pham, Q.T., D. Teculescu, C. Me yer-Bisch, and J.M. Mur. 1988. Ef fects of chronic exposure to diisocyanates. Bull. Eur. Physiopathol. Respir. 23: 561-564.

Reuzel, P.G.J., J.H.E. Arts , M.H.M. Kuypers, and C. F. Kuper. 1990. Chronic toxicity/carcinogenicity inhalation study of po lymeric methylene diphenyl diisocyanate aerosol in rats. Prepared by the Civo Institute for the International Isocyanate Institute. Report No. V 88.122, 1990.

Reuzel, P.G.J., M.S. Bosland, L.M. Appelman, A.W.J. de Jong , and J.P. Bruyntjes. 1985a. Subchronic (13 week) inhalation toxi city study of polymeric MDI aero sol in rats (part B1) (Final Report). Prepared by Civo Institute for the In ternational Isocyanate Institute. January 1985. Report No. V83.290/220758.
Reuzel, P.G.J., C.F. Kuper, L.M. Appelman, and R.N. Hooftman. 1985b. Sub-chronic (13 week) inhalation toxicity study of polymeric MDI aerosol in rats (part B2) (Final report). Prepared by the Civo Institute for the International Isocyanate Institute. January 1985. Report No. V85.023/240158.

Reuzel, P.G.J., J.H.E. Arts, L.G. Lomax, et al . 1994b. Chronic inhalation and carcinogenicity study of respirable polymeric me thylene diphenyl diisocyanate (p olymeric MDI) aerosol in rats. Fundam. Appl. Toxicol. 22: 195-210.
Reuzel, P.G.J., C.F. Kuper, V.J. Feron, L.M. Appelman, and E. Loser. 1994a. Acute, subacute, and subchronic inhalation toxicity studies of respirable polymeric methylene diphenyl diisocyanate (polymeric MDI) aerosol in rats. Fundam. Appl. Toxicol. 22: 186-194.

Tanser, A.R., M.P. Bourke, and A.G. Blandf ord. 1973. Isocyanate asthma: respiratory symptoms caused by diphenyl-methane di-isocyanate. Thorax 28: 596-600.

Tse, K.S., A. Johnson, H. Chan , and M. Chan-Yeung. 1985. A stud y of serum antibody activity in workers with occupational exposure to diph enyl methane diisocyana te. Allergy 40: 314-320.
Tyl, R.W. 1988. Developmental toxicity study of inhaled toluene diisocyanate vapor in CD (Sprague-Dawley) rats. Union Ca rbide, Bushy Run Rese arch Center. Revised Project Report 50- 592.
Tyl, R.W., and T.L. Neeper-Bradley. 1989. Tw o-generation reproduct ion study of inhaled toluene diisocyanate in CD (Sprague-Dawley) rats. Union Carbide, Bush y Run Research Center. Project Number 86-33-90704.
Ulrich, H. 1983. Urethane polymers. Kirk-Othme r Encyclopedia of Chemical Technology, 3rd ed., Vol 23. pp. 576-608.
U.S. EPA. 1994. Interim Policy for Particle Size and Limit Concentration Issues in Inhalation Toxicity: Notice of Availability, dated October 26, 1994. Fed. Reg. 59 (206):53799.

U.S. EPA. 1994a. Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry, EPA/600/8-90/066F, dated October 1994.
U.S. EPA. 1998. Toxicological Review of Methyl ene Diphenyl Diisocyanate. For Internet access see www.epa.gov/iris , or contact the IRIS Hotline at(202)566-1676 (phone), (202)566-1749 

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8/9/2011 http ://www.ep a. g ov/iris/subst/0529.htm(fax), or hotline.iris@epa.gov (Internet address).
Vandenplas, O., J.-L. Malo, M. Saetta, C.E. Mapp, and L.M. Fabbri. 1993 Occupational asthma and extrinsic alveolitis due to is ocyanates: current status and pers pectives. Br. J. Ind. Med. 50: 213-228.
Zammit-Tabona, M., M. Sherkin, K. Kijek, H. Chan, and M. Chan-Yeung. 1983. Asthma caused by diphenylmethane diisocyanate in foundry workers. Am. Rev. Respir. Dis. 128: 226-230.

Zeiss, C.R., T.M. Kannellakes, J. D. Bellone, D. Levitz, J.J. Pr uzansky, and R. Patterson. 1980.Immunoglobulin E-mediated asthma and hypersensitivity pneumonitis with precipitating antihapten antibodies due to diphenylmethane di isocyanate (MDI) exposu re. J. Allergy Clin. Immunol. 65(5): 346-352.

_VI.C. Carcinogenicity Assessment References
Andersen, M., M.-L. Binderup, P. Kiel, H. Lars en and J. Maxild. 1980. Mutagenic action of isocyanates used in the production of polyuretha nes. Scand. J. Work environ. Health 6: 221- 226.

Gahlmann, R., B. Herbold, A. Ruckes and K. S eel. Untersuchungen zur Stabilitat aromatischer Diisocyanate in dimethylsulfoxid (D MSO): Toluylendiisocynat (TDI) und Diphenylmethandiisocyanat (MDI) im Ames -Test. Zbl. Arbeit smed. 43: 34-38.
Hagmar, L., H. Welinder, and Z. Mikoczy. 1993a. Cancer incidenc e and mortality in the Swedish polyurethane foam manufacturing indu stry. Br. J. Ind. Med. 50: 537-543.
Hagmar, L., U. Stromberg, H. Welinder, and Z. Mikoczy. 1993b. Incidence of cancer and exposure to toluene diisocyanate and methylen e diphenyldiisocyanate; a cohort based casereferent study in the polyuret hane foam manufacturing indust ry. Br. J. Ind. Med. 50: 1003- 1007.
Hengler, W.C. and R.S. Sles inski. 1982. Diphenylmethan e diisocyanate prepolymer. Salmonella/microsome (Ames) bacterial mutagenicity assay. Bushy Run Research Center, Union Carbide. Project Report 45-65.
Haskell Laboratory. 1976. In vitro microbia l mutagenicity studies of isocyanic acid, methylenedi-para-phenylene ester. E.I. du Pont de Nemours and Company. Haskell Laboratory Report No. 463-76.
Hoymann, H.-G., J. Buschmann , and U. Heinrich. 1995. Exam inations about the chronic toxicity/carcinogenicity of 4,4' -methylene diphenyl diisocyanate (MDI). Fraunhofer-Institut fur Toxikologie and Aerosolforshung, Hannov er, Germany. ReportNo. 116-06-084.
Loeser, E. 1983. Long-term toxicity and carc inogenicity studies wi th 2,4/2,6-toluenediisocyanate (80/20) in rats and mice. Toxicol. Lett. 15: 71-81.
Maki-Paakkenen, J. and H. Norppa. 1987. Ch romosome aberrations and sister- chromatid exchanges induced by technical grade toluene diisocyanate and methylene diphenyl diisocyanate in cultured human lymp hocytes. Toxicol. Lett. 36: 37-43. 

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8/9/2011 http ://www.ep a. g ov/iris/subst/0529.htmMarczynski, B., A.B. Czuppon, H.P. Hoffarth, W. Marek and X. Baur. 1992. DNA damage in human white blood cells after inhalation exposure to methylene diphenyl diisocyanate (MDI) - case report. Toxicol. Lett. 60: 131-138.

Reuzel, P.G.J., J.H.E. Arts, L.G. Lomax, M.H.M. Kuijpers, C.F. Kuper, C. Gembardt, V.J. Feron and E. Loser. 1994a. Chronic inhalation and ca rcinogenicity study of respirable polymeric methylene diphenyl diisocyanate (polymeric MDI) aerosol in rats. Fundam. Appl. Toxicol. 22: 195-210.
Reuzel, P.G.J., C.F. Kuper, V.J. Feron, L.M. Appelman, and E. Loser. 1994b. Acute, subacute, and subchronic inhalation toxicity studies of respirable polymeric methylene diphenyl diisocyanate (polymeric MDI) aerosol in rats. Fundam. Appl. Toxicol. 22: 186-194.

Reuzel, P.G.J., J.H.E. Arts , M.H.M. Kuypers, and C. F. Kuper. 1990. Chronic toxicity/carcinogenicity inhalation study of po lymeric methylene diphenyl diisocyanate aerosol in rats. Prepared by the Civo Institute for the International Isocyanate Institute. Report No. V 88.122, 1990.
Sepai, O., D. Henschler and G. Sabbioni. 1995. Albumin addu cts, hemoglobin adducts and urinary metabolites in workers exposed to 4,4'-m ethylenediphenyl diisocyanate. Carcinogenesis 16(10): 2583-2587.
Sorahan, T. and D. Pope. 1993. Mortality and cancer morbidity of production workers in the United Kingdom flexible polyurethane foam industry. Br. J. Ind. Med. 50: 528-536.
Ulrich, H. 1983. Urethane Polyme rs. Kirk-Othmer encyclopedia of chemical technology, 3rd Ed., Vol. 23. pp. 576-608.
U.S. Environmental Protection Agency. 1996. Proposed guidelines for carcinogen risk assessment. Federal Register 61(79): 17960-18011.
U.S. Environmental Protection Agency. 1986. Ri sk assessment guidelines of 1986. Office of Health and Environmental Assessment, Washington, DC. EPA/600/8-87/045.



### _VII. Revision History
Methylene Diphenyl (monomeric MDI) and polymeric MDI (PMDI) CASRN — 101-68-8, 9016-87-9

Date Section Descri p tion 08/01/1991 I.B. Inhalation RfC now under review 03/01/1993 I.B. Work group review data added
05/01/1994 I.B. Inhalation RfC now on-line
05/01/1994 VI.B. Inhalation RfC references on-line 04/01/1997 III., IV., V. Drinking Water Health Advisories , EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program 

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### _VIII. Synonyms
Methylene Diphenyl Diisocyanate (monom eric MDI) and polymeric MDI (PMDI) CASRN — 101-68-8, 9016-87-9 Last Revised —02/07/1998

101-68-8 1,1' - METHYLENEBIS (4-ISOCYANATOBENZENE) 4,4' - DIISOCIANATO DE DIFENILMETANO (SPANISH) 4,4' - DIISOCYANATE DE DIPHENYLMETHANE (FRENCH) 4,4' - DIISOCYANATH ODIPHENYLMETHANE 4,4' - DIPHENYLMETHANE DILSOCYANATE 4,4' - METHYLENEBIS (PHENYL ISOCYANATE) 4,4' - METHYLENEDIPHENYL DIISOCYANATE 4,4' - METHYLENEDIPHENYLENE ISOCYANATE 4,4' - METHYLENEDI - P- PHENYLENE DIISOCYANATE BENZENE, 1,1' -METHYLE NEBIS(4-ISOCYANATOBIS (1,4-ISOCYANATHOPHENYL) METHANE BIS (4-ISOCYANATOPHENYL) METHANE BIS (P-ISOCYANATOPHENYL) METHANE CARADATE 30 DESMODUR 44 DI-(4-ISOCYANATOPHENYL) METHANE DIFENIL-METHAN-DIISOC IANATO (ITALIAN) DIFENYLMETHAAN-DISSOCYANAAT (DUTCH) DIISOCYANATE DE DIOPHENYLMETHANE-4,4' (FRENCH) DIPHENYLMETHAN-4,4' -DII SOCYANAT (GERMAN) DIPHENYLMETHANE 4,4' -DIISOCYANATE DIPHENYLMETHANE-4,4' -DIISOCYANATE DIPHENYL METHANE DIISOCYANATE DIPHENYLMETHANE DIISOCYANATE HSDB 2630 HYLENE M50 ISOCYANIC ACID ISONATE 125M ISONATE 125 MF MDI METHYLENEBIS (4-ISOCYANATOBENENE) METHYLENEBIS (4-PHENYLENE ISOCYANATE) METHYLENEBIS (4-PHENYL ISOCYANATE) METHYLENEBIS (4-PHENYLISOCYANATE) METHYLENEBIS (P-PHENYLENE ISOCYANATE) METHYLENEBIS (P-PHENYL ISOCYANATE) METHYLENE DI (PHENYLENE ISOCYANATE) METHYLENEDI-P-PHENYLENE DIISOCYANATE METHYLENEDI-P-PHENYLENE ESTER METHYLENEDI-P-PHENYLENE ISOCYANATE NACCONATE 300 NCI-C50668 NSC 9596 Offices for this information. 02/07/1998 I.B., II., VI. Revised RfC, new carcinogenicity assessment

12/03/2002 I.B.6., II.D.2. Screening-Level Literature Review Findings message has been added. 

### Iris Camacho, 6308MM Pa g e 17 of 19 Meth y lene Dipheny l Diisoc y anate (monomeric MDI) and pol y

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8/9/2011 http ://www.ep a. g ov/iris/subst/0529.htmP,P' -DIPOHENYLMETHANE DIISOCYANATE P,P' -METHYLENEBIS (PHENYL ISOCYANATE) UN 2489

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### Iris Camacho, 6308MM Pa g e 18 of 19 Meth y lene Dipheny l Diisoc y anate (monomeric MDI) and pol y

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8/9/2011 http ://www.ep a. g ov/iris/subst/0529.htmEstimate of Carcinogenic Risk from Oral Exposure Summary of Risk Estimates Dose-Response Data Additional Comments Discussion of Confidence
Quantitative Estimate of Carcinogenic Risk

from Inhalation Exposure Summary of Risk Estimates Dose-Response Data Additional Comments Discussion of Confidence EPA Documentation, Review and, Contacts Bibliography Revision History Synonyms 

### Iris Camacho, 6308MM Pa g e 19 of 19 Meth y lene Dipheny l Diisoc y anate (monomeric MDI) and pol y

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8/9/2011 http ://www.ep a. g ov/iris/subst/0529.htm